Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Nathalie Chami; Ming Huei Chen; Andrew J. Slater; John D. Eicher; Evangelos Evangelou; Salman M. Tajuddin; Latisha Love-Gregory; Tim Kacprowski; Ursula M. Schick; Akihiro Nomura; Ayush Giri; Samuel Lessard; Jennifer A. Brody; Claudia Schurmann; Nathan Pankratz; Lisa R. Yanek; Ani Manichaikul; Raha Pazoki; Evelin Mihailov; W. David Hill; Laura M. Raffield; Amber Burt; Traci M. Bartz; Diane M. Becker; Lewis C. Becker; Eric Boerwinkle; Jette Bork-Jensen; Erwin P. Bottinger; Michelle L. O'Donoghue; David R. Crosslin; Simon de Denus; Marie Pierre Dubé; Paul Elliott; Gunnar Engström; Michele K. Evans; James S. Floyd; Myriam Fornage; He Gao; Andreas Greinacher; Vilmundur Gudnason; Torben Hansen; Tamara B. Harris; Caroline Hayward; Jussi Hernesniemi; Heather M. Highland; Joel N. Hirschhorn; Albert Hofman; Marguerite R. Irvin; Mika Kähönen; Ethan Lange; Lenore J. Launer; Terho Lehtimäki; Jin Li; David C.M. Liewald; Allan Linneberg; Yongmei Liu; Yingchang Lu; Leo Pekka Lyytikäinen; Reedik Mägi; Rasika A. Mathias; Olle Melander; Andres Metspalu; Nina Mononen; Mike A. Nalls; Deborah A. Nickerson; Kjell Nikus; Chris J. O'Donnell; Marju Orho-Melander; Oluf Pedersen; Astrid Petersmann; Linda Polfus; Bruce M. Psaty; Olli T. Raitakari; Emma Raitoharju; Melissa Richard; Kenneth M. Rice; Fernando Rivadeneira; Jerome I. Rotter; Frank Schmidt; Albert Vernon Smith; John M. Starr; Kent D. Taylor; Alexander Teumer; Betina H. Thuesen; Eric S. Torstenson; Russell P. Tracy; Ioanna Tzoulaki; Neil A. Zakai; Caterina Vacchi-Suzzi; Cornelia M. van Duijn; Frank J.A. van Rooij; Mary Cushman; Ian J. Deary; Digna R. Velez Edwards; Anne Claire Vergnaud; Lars Wallentin; Dawn M. Waterworth; Harvey D. White; James G. Wilson; Alan B. Zonderman; Sekar Kathiresan; Niels Grarup; Tõnu Esko; Ruth J.F. Loos; Leslie A. Lange; Nauder Faraday; Nada A. Abumrad; Todd L. Edwards; Santhi K. Ganesh; Paul L. Auer; Andrew D. Johnson; Alexander P. Reiner; Guillaume Lettre

doi:10.1016/j.ajhg.2016.05.007

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Nathalie Chami, Ming Huei Chen, Andrew J. Slater, John D. Eicher, Evangelos Evangelou, Salman M. Tajuddin, Latisha Love-Gregory, Tim Kacprowski, Ursula M. Schick, Akihiro Nomura, Ayush Giri, Samuel Lessard, Jennifer A. Brody, Claudia Schurmann, Nathan Pankratz, Lisa R. Yanek, Ani Manichaikul, Raha Pazoki, Evelin Mihailov, W. David HillLaura M. Raffield, Amber Burt, Traci M. Bartz, Diane M. Becker, Lewis C. Becker, Eric Boerwinkle, Jette Bork-Jensen, Erwin P. Bottinger, Michelle L. O'Donoghue, David R. Crosslin, Simon de Denus, Marie Pierre Dubé, Paul Elliott, Gunnar Engström, Michele K. Evans, James S. Floyd, Myriam Fornage, He Gao, Andreas Greinacher, Vilmundur Gudnason, Torben Hansen, Tamara B. Harris, Caroline Hayward, Jussi Hernesniemi, Heather M. Highland, Joel N. Hirschhorn, Albert Hofman, Marguerite R. Irvin, Mika Kähönen, Ethan Lange, Lenore J. Launer, Terho Lehtimäki, Jin Li, David C.M. Liewald, Allan Linneberg, Yongmei Liu, Yingchang Lu, Leo Pekka Lyytikäinen, Reedik Mägi, Rasika A. Mathias, Olle Melander, Andres Metspalu, Nina Mononen, Mike A. Nalls, Deborah A. Nickerson, Kjell Nikus, Chris J. O'Donnell, Marju Orho-Melander, Oluf Pedersen, Astrid Petersmann, Linda Polfus, Bruce M. Psaty, Olli T. Raitakari, Emma Raitoharju, Melissa Richard, Kenneth M. Rice, Fernando Rivadeneira, Jerome I. Rotter, Frank Schmidt, Albert Vernon Smith, John M. Starr, Kent D. Taylor, Alexander Teumer, Betina H. Thuesen, Eric S. Torstenson, Russell P. Tracy, Ioanna Tzoulaki, Neil A. Zakai, Caterina Vacchi-Suzzi, Cornelia M. van Duijn, Frank J.A. van Rooij, Mary Cushman, Ian J. Deary, Digna R. Velez Edwards, Anne Claire Vergnaud, Lars Wallentin, Dawn M. Waterworth, Harvey D. White, James G. Wilson, Alan B. Zonderman, Sekar Kathiresan, Niels Grarup, Tõnu Esko, Ruth J.F. Loos, Leslie A. Lange, Nauder Faraday, Nada A. Abumrad, Todd L. Edwards, Santhi K. Ganesh, Paul L. Auer, Andrew D. Johnson, Alexander P. Reiner, Guillaume Lettre

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10⁻¹⁰ for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10⁻⁸ for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10⁻¹¹) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10⁻⁹). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10⁻⁷). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Original language	English
Pages (from-to)	8-21
Number of pages	14
Journal	American journal of human genetics
Volume	99
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2016.05.007
State	Published - Jul 7 2016

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Chami, N., Chen, M. H., Slater, A. J., Eicher, J. D., Evangelou, E., Tajuddin, S. M., Love-Gregory, L., Kacprowski, T., Schick, U. M., Nomura, A., Giri, A., Lessard, S., Brody, J. A., Schurmann, C., Pankratz, N., Yanek, L. R., Manichaikul, A., Pazoki, R., Mihailov, E., ... Lettre, G. (2016). Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. American journal of human genetics, 99(1), 8-21. https://doi.org/10.1016/j.ajhg.2016.05.007

@article{b0c038b4063042b7b4f7c928c5dab3e5,

title = "Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits",

abstract = "Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10−10 for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10−8 for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10−11) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10−9). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10−7). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.",

author = "Nathalie Chami and Chen, {Ming Huei} and Slater, {Andrew J.} and Eicher, {John D.} and Evangelos Evangelou and Tajuddin, {Salman M.} and Latisha Love-Gregory and Tim Kacprowski and Schick, {Ursula M.} and Akihiro Nomura and Ayush Giri and Samuel Lessard and Brody, {Jennifer A.} and Claudia Schurmann and Nathan Pankratz and Yanek, {Lisa R.} and Ani Manichaikul and Raha Pazoki and Evelin Mihailov and Hill, {W. David} and Raffield, {Laura M.} and Amber Burt and Bartz, {Traci M.} and Becker, {Diane M.} and Becker, {Lewis C.} and Eric Boerwinkle and Jette Bork-Jensen and Bottinger, {Erwin P.} and O'Donoghue, {Michelle L.} and Crosslin, {David R.} and {de Denus}, Simon and Dub{\'e}, {Marie Pierre} and Paul Elliott and Gunnar Engstr{\"o}m and Evans, {Michele K.} and Floyd, {James S.} and Myriam Fornage and He Gao and Andreas Greinacher and Vilmundur Gudnason and Torben Hansen and Harris, {Tamara B.} and Caroline Hayward and Jussi Hernesniemi and Highland, {Heather M.} and Hirschhorn, {Joel N.} and Albert Hofman and Irvin, {Marguerite R.} and Mika K{\"a}h{\"o}nen and Ethan Lange and Launer, {Lenore J.} and Terho Lehtim{\"a}ki and Jin Li and Liewald, {David C.M.} and Allan Linneberg and Yongmei Liu and Yingchang Lu and Lyytik{\"a}inen, {Leo Pekka} and Reedik M{\"a}gi and Mathias, {Rasika A.} and Olle Melander and Andres Metspalu and Nina Mononen and Nalls, {Mike A.} and Nickerson, {Deborah A.} and Kjell Nikus and O'Donnell, {Chris J.} and Marju Orho-Melander and Oluf Pedersen and Astrid Petersmann and Linda Polfus and Psaty, {Bruce M.} and Raitakari, {Olli T.} and Emma Raitoharju and Melissa Richard and Rice, {Kenneth M.} and Fernando Rivadeneira and Rotter, {Jerome I.} and Frank Schmidt and Smith, {Albert Vernon} and Starr, {John M.} and Taylor, {Kent D.} and Alexander Teumer and Thuesen, {Betina H.} and Torstenson, {Eric S.} and Tracy, {Russell P.} and Ioanna Tzoulaki and Zakai, {Neil A.} and Caterina Vacchi-Suzzi and {van Duijn}, {Cornelia M.} and {van Rooij}, {Frank J.A.} and Mary Cushman and Deary, {Ian J.} and {Velez Edwards}, {Digna R.} and Vergnaud, {Anne Claire} and Lars Wallentin and Waterworth, {Dawn M.} and White, {Harvey D.} and Wilson, {James G.} and Zonderman, {Alan B.} and Sekar Kathiresan and Niels Grarup and T{\~o}nu Esko and Loos, {Ruth J.F.} and Lange, {Leslie A.} and Nauder Faraday and Abumrad, {Nada A.} and Edwards, {Todd L.} and Ganesh, {Santhi K.} and Auer, {Paul L.} and Johnson, {Andrew D.} and Reiner, {Alexander P.} and Guillaume Lettre",

note = "Publisher Copyright: {\textcopyright} 2016 American Society of Human Genetics",

year = "2016",

month = jul,

day = "7",

doi = "10.1016/j.ajhg.2016.05.007",

language = "English",

volume = "99",

pages = "8--21",

journal = "American journal of human genetics",

issn = "0002-9297",

number = "1",

}

Chami, N, Chen, MH, Slater, AJ, Eicher, JD, Evangelou, E, Tajuddin, SM, Love-Gregory, L, Kacprowski, T, Schick, UM, Nomura, A, Giri, A, Lessard, S, Brody, JA, Schurmann, C, Pankratz, N, Yanek, LR, Manichaikul, A, Pazoki, R, Mihailov, E, Hill, WD, Raffield, LM, Burt, A, Bartz, TM, Becker, DM, Becker, LC, Boerwinkle, E, Bork-Jensen, J, Bottinger, EP, O'Donoghue, ML, Crosslin, DR, de Denus, S, Dubé, MP, Elliott, P, Engström, G, Evans, MK, Floyd, JS, Fornage, M, Gao, H, Greinacher, A, Gudnason, V, Hansen, T, Harris, TB, Hayward, C, Hernesniemi, J, Highland, HM, Hirschhorn, JN, Hofman, A, Irvin, MR, Kähönen, M, Lange, E, Launer, LJ, Lehtimäki, T, Li, J, Liewald, DCM, Linneberg, A, Liu, Y, Lu, Y, Lyytikäinen, LP, Mägi, R, Mathias, RA, Melander, O, Metspalu, A, Mononen, N, Nalls, MA, Nickerson, DA, Nikus, K, O'Donnell, CJ, Orho-Melander, M, Pedersen, O, Petersmann, A, Polfus, L, Psaty, BM, Raitakari, OT, Raitoharju, E, Richard, M, Rice, KM, Rivadeneira, F, Rotter, JI, Schmidt, F, Smith, AV, Starr, JM, Taylor, KD, Teumer, A, Thuesen, BH, Torstenson, ES, Tracy, RP, Tzoulaki, I, Zakai, NA, Vacchi-Suzzi, C, van Duijn, CM, van Rooij, FJA, Cushman, M, Deary, IJ, Velez Edwards, DR, Vergnaud, AC, Wallentin, L, Waterworth, DM, White, HD, Wilson, JG, Zonderman, AB, Kathiresan, S, Grarup, N, Esko, T, Loos, RJF, Lange, LA, Faraday, N, Abumrad, NA, Edwards, TL, Ganesh, SK, Auer, PL, Johnson, AD, Reiner, AP & Lettre, G 2016, 'Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits', American journal of human genetics, vol. 99, no. 1, pp. 8-21. https://doi.org/10.1016/j.ajhg.2016.05.007

TY - JOUR

T1 - Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

AU - Chami, Nathalie

AU - Chen, Ming Huei

AU - Slater, Andrew J.

AU - Eicher, John D.

AU - Evangelou, Evangelos

AU - Tajuddin, Salman M.

AU - Love-Gregory, Latisha

AU - Kacprowski, Tim

AU - Schick, Ursula M.

AU - Nomura, Akihiro

AU - Giri, Ayush

AU - Lessard, Samuel

AU - Brody, Jennifer A.

AU - Schurmann, Claudia

AU - Pankratz, Nathan

AU - Yanek, Lisa R.

AU - Manichaikul, Ani

AU - Pazoki, Raha

AU - Mihailov, Evelin

AU - Hill, W. David

AU - Raffield, Laura M.

AU - Burt, Amber

AU - Bartz, Traci M.

AU - Becker, Diane M.

AU - Becker, Lewis C.

AU - Boerwinkle, Eric

AU - Bork-Jensen, Jette

AU - Bottinger, Erwin P.

AU - O'Donoghue, Michelle L.

AU - Crosslin, David R.

AU - de Denus, Simon

AU - Dubé, Marie Pierre

AU - Elliott, Paul

AU - Engström, Gunnar

AU - Evans, Michele K.

AU - Floyd, James S.

AU - Fornage, Myriam

AU - Gao, He

AU - Greinacher, Andreas

AU - Gudnason, Vilmundur

AU - Hansen, Torben

AU - Harris, Tamara B.

AU - Hayward, Caroline

AU - Hernesniemi, Jussi

AU - Highland, Heather M.

AU - Hirschhorn, Joel N.

AU - Hofman, Albert

AU - Irvin, Marguerite R.

AU - Kähönen, Mika

AU - Lange, Ethan

AU - Launer, Lenore J.

AU - Lehtimäki, Terho

AU - Li, Jin

AU - Liewald, David C.M.

AU - Linneberg, Allan

AU - Liu, Yongmei

AU - Lu, Yingchang

AU - Lyytikäinen, Leo Pekka

AU - Mägi, Reedik

AU - Mathias, Rasika A.

AU - Melander, Olle

AU - Metspalu, Andres

AU - Mononen, Nina

AU - Nalls, Mike A.

AU - Nickerson, Deborah A.

AU - Nikus, Kjell

AU - O'Donnell, Chris J.

AU - Orho-Melander, Marju

AU - Pedersen, Oluf

AU - Petersmann, Astrid

AU - Polfus, Linda

AU - Psaty, Bruce M.

AU - Raitakari, Olli T.

AU - Raitoharju, Emma

AU - Richard, Melissa

AU - Rice, Kenneth M.

AU - Rivadeneira, Fernando

AU - Rotter, Jerome I.

AU - Schmidt, Frank

AU - Smith, Albert Vernon

AU - Starr, John M.

AU - Taylor, Kent D.

AU - Teumer, Alexander

AU - Thuesen, Betina H.

AU - Torstenson, Eric S.

AU - Tracy, Russell P.

AU - Tzoulaki, Ioanna

AU - Zakai, Neil A.

AU - Vacchi-Suzzi, Caterina

AU - van Duijn, Cornelia M.

AU - van Rooij, Frank J.A.

AU - Cushman, Mary

AU - Deary, Ian J.

AU - Velez Edwards, Digna R.

AU - Vergnaud, Anne Claire

AU - Wallentin, Lars

AU - Waterworth, Dawn M.

AU - White, Harvey D.

AU - Wilson, James G.

AU - Zonderman, Alan B.

AU - Kathiresan, Sekar

AU - Grarup, Niels

AU - Esko, Tõnu

AU - Loos, Ruth J.F.

AU - Lange, Leslie A.

AU - Faraday, Nauder

AU - Abumrad, Nada A.

AU - Edwards, Todd L.

AU - Ganesh, Santhi K.

AU - Auer, Paul L.

AU - Johnson, Andrew D.

AU - Reiner, Alexander P.

AU - Lettre, Guillaume

PY - 2016/7/7

Y1 - 2016/7/7

N2 - Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10−10 for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10−8 for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10−11) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10−9). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10−7). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

AB - Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10−10 for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10−8 for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10−11) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10−9). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10−7). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

UR - http://www.scopus.com/inward/record.url?scp=84989865856&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.05.007

DO - 10.1016/j.ajhg.2016.05.007

M3 - Article

C2 - 27346685

AN - SCOPUS:84989865856

SN - 0002-9297

VL - 99

SP - 8

EP - 21

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

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